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PubMedDate not supplied

Neurobiology of central angiotensin III and dipsogenesis.

This review provides a synopsis of the physiologic role of central angiotensin III (AIII), the biologically active degradative product of angiotensin II, in dipsogenesis. The integrity of the central noradrenergic system is essential to the elicitation of polydipsia by AIII. It is conceivable that synaptically released norepinephrine may act on the alpha 1-adrenoceptors to potentiate the drinking response to the heptapeptide. This release, however, may be subjected to a tonic inhibition by the alpha 2-adrenoceptors. Chronic intracerebroventricular administration of AIII fails to produce sustained drinking behavior in spontaneously hypertensive rats. Behavioral and electrophysiologic observations suggest that this is because of the development of early desensitization of at least the angiotensin receptors at the subfornical organ, a major target site for AIII-induced dipsogenesis. This process is exacerbated by a suggested dysfunction of the central degradative enzyme for AIII in this strain of rat. Recent results suggest that it is likely that neurons in the caudal hypoglossal nucleus may serve as the final common pathway for AIII-induced drinking response. Furthermore, an excitatory link between the nucleus reticularis gigantocellularis in the medulla oblongata and caudal hypoglossal nucleus may form part of the descending neural pathways that mediate the dipsogenesis elicited by AIII. It is evident that AIII in the brain participates actively in at least the initiation and consummatory phases of water homeostasis. Thus, apart from directly acting on the central machinery for circulatory control, AIII may also influence cardiovascular functions by affecting cardiac output via regulation of fluid volume.

Angiotensin III↗

PubMed2005

Neural differentiation of mouse embryonic stem cells in chemically defined medium.

Directed differentiation of embryonic stem (ES) cells has enormous potential to derive a wide variety of defined cell populations of therapeutic value. To achieve this, it is necessary to use protocols that promote cell differentiation under defined culture conditions. Furthermore, understanding the mechanisms of cell differentiation in vitro will allow the development of rationale approaches to systematically manipulate cell fates. Here we have analysed the differentiation of mouse ES cells to the neural lineage under serum and feeder cell-free conditions, using a previously described chemically defined medium (CDM). In CDM, ES cell differentiation is highly neurogenic. Cell differentiation was monitored by analysis of a gene expression array (Clontech-Atlas) and by semi-quantitative RT-PCR for a panel of genes involved in cell lineage specification and patterning of the epiblast. In addition to expression of neural markers, data identified a transient expression of several genes associated with the organising activities of the embryonic node and visceral endoderm, including regulators of WNT, BMP, Hedgehog and FGF signaling pathways. Neural differentiation in CDM does not occur by a simple default mechanism, but was dependent on endogenous FGF signaling, and could be blocked by adding BMP4, and LiCl to simulate WNT activation. Neural differentiation was also inhibited by antagonising endogenous hedgehog activity. Taken together the profile of gene expression changes seen in CDM cultures recapitulates those seen in the early embryo, and is suggestive of common developmental mechanisms.

Animals↗

PubMed1998

Calcium imaging and multielectrode recordings of global patterns of activity in the developing nervous system.

Complex but coordinated interactions involving ensembles of neuronal cells result in the accurate processing of information in the adult central nervous system. However, recent studies monitoring the global patterns of activity of neuronal populations have demonstrated that immature neurons also interact to produce coordinated patterns of activity during the early stages of development. In particular, these patterns of coordinated activity occur during the period when neuronal connections are established, thus leading us to believe that such activity patterns might underlie the precision to which many neural pathways are wired up. Multielectrode recording and calcium imaging are two of the techniques that have been instrumental in revealing the spatial and temporal properties of the coordinated activity of developing neural networks in vitro. While multielectrode arrays measure the action potential activity of the cells, calcium imaging permits changes in intracellular calcium levels to be monitored over time. Both techniques have been used successfully to monitor the activity of cellular networks in culture, but they have also been applied in assessing the patterns of activity in intact or semi-intact pieces of neural tissues, such as the developing retina, neocortex and spinal cord. More recently, it has also been possible to correlate the structure and function of the cellular components of the networks by combining intracellular dye filling with the multineuronal recordings. In this review, brief descriptions and the applications of the two techniques will be presented, and the advantages and limitations of multielectrode array will be compared with that of calcium imaging using recordings of the developing mammalian retina as the primary example.

Action Potentials↗

PubMed1984

Pain and analgesia: the outlook for more rational treatment.

Recent advances have been made in research on the physiology of pain, especially that focusing on the primary afferent nociceptor and endogenous analgesia systems. These advances have shed new light on the mechanisms of action of some long-used methods of managing pain, have led to the development of several methods, and have suggested new lines of investigation that may lead to more rational treatment of pain. The earlier that we can intervene in the pain-transmission pathways, the more likely we are to produce adequate and lasting control of pain. The peripheral nervous system is an important target for this therapeutic approach. The elucidation of the central neural pathways, which contain endogenous opioids and mediate the analgesia elicited by opiates, has raised the possibility of more rational use of this class of analgesics. The rationale for the use of current therapies needs to be reexamined in light of these new findings, and both current and new methods need to be tested in controlled trials.

Afferent Pathways↗

PubMed2004

Mapping the neural substrate underlying brain stimulation reward with the behavioral adaptation of double-pulse methods.

Behavioral adaptations of double-pulse methods--primarily collision and refractory period tests--have been employed to unveil the electrophysiological and anatomical characteristics of neural networks of known function. These paradigms are based on trade-off functions: a determination of different combinations of stimuli that yield the same behavioral output. A detailed explanation of the logic and methodology underlying these techniques is elaborated in this paper. The implementation of such approaches to the study of brain stimulation reward (BSR) has provided a means of discriminating between the neurons underlying this behavior from other cells activated by the stimulating electrode, endowing them with a particularly powerful scientific scope. An increasingly detailed portrait of the BSR substrate, both within and outside the medial forebrain bundle, has been emerging as a result of these investigations and is reviewed in this paper. Finally, the challenges associated with these paradigms are discussed and potential solutions as well as future experimental ventures proposed. Attention is drawn to the major contribution of these methods to our understanding of the neural pathways and characteristics underlying BSR.

Adaptation, Physiological↗

PubMed1992

The role of the amygdala in fear-potentiated startle: implications for animal models of anxiety.

Over the past several years, major advances have been made in understanding the pharmacology of anxiety, involving three broad classes of experimental approach. One approach studies the mechanism of action of drugs that are known to treat anxiety clinically, such as the benzodiazepines. A second approach uses various animal models of fear or anxiety that are sensitive to known anxiolytic drugs, to see if they will detect new compounds. A third approach involves describing the neural pathways and neurotransmitters that are active in a state of fear or anxiety; importantly, this approach is not derived from the mechanisms of known anxiolytics. In this review, Michael Davis describes such a 'neural systems' approach to the study of fear or anxiety that uses the paradigm of fear-potentiated startle.

Amygdala↗

PubMed2003

Associative learning and memory in Drosophila: beyond olfactory conditioning.

The associative learning abilities of the fruit fly, Drosophila melanogaster, have been demonstrated in both classical and operant conditioning paradigms. Efforts to identify the neural pathways and cellular mechanisms of learning have focused largely on olfactory classical conditioning. Results derived from various genetic and molecular manipulations provide considerable evidence that this form of associative learning depends critically on neural activity and cAMP signaling in brain neuropil structures called mushroom bodies. Three other behavioral learning paradigms in Drosophila serve as the main subject of this review. These are (1) visual and motor learning of flies tethered in a flight simulator, (2) a form of spatial learning that is independent of visual and olfactory cues, and (3) experience-dependent changes in male courtship behavior. The present evidence suggests that at least some of these modes of learning are independent of mushroom bodies. Applying targeted genetic manipulations to these behavioral paradigms should allow for a more comprehensive understanding of neural mechanisms responsible for diverse forms of associative learning and memory.

Journal Article↗

PubMed2006

Comparison of midbrain and thalamic space-specific neurons in barn owls.

Spatial receptive fields of neurons in the auditory pathway of the barn owl result from the sensitivity to combinations of interaural time (ITD) and level differences across stimulus frequency. Both the forebrain and tectum of the owl contain such neurons. The neural pathways, which lead to the forebrain and tectal representations of auditory space, separate before the midbrain map of auditory space is synthesized. The first nuclei that belong exclusively to either the forebrain or the tectal pathways are the nucleus ovoidalis (Ov) and the external nucleus of the inferior colliculus (ICx), respectively. Both receive projections from the lateral shell subdivision of the inferior colliculus but are not interconnected. Previous studies indicate that the owl's tectal representation of auditory space is different from those found in the owl's forebrain and the mammalian brain. We addressed the question of whether the computation of spatial cues in both pathways is the same by comparing the ITD tuning of Ov and ICx neurons. Unlike in ICx, the relationship between frequency and ITD tuning had not been studied in single Ov units. In contrast to the conspicuous frequency independent ITD tuning of space-specific neurons of ICx, ITD selectivity varied with frequency in Ov. We also observed that the spatially tuned neurons of Ov respond to lower frequencies and are more broadly tuned to ITD than in ICx. Thus there are differences in the integration of frequency and ITD in the two sound-localization pathways. Thalamic neurons integrate spatial information not only within a broader frequency band but also across ITD channels.

Acoustic Stimulation↗

PubMed1993

Bilateral inhibition generates neuronal responses tuned to interaural level differences in the auditory brainstem of the barn owl.

I investigated the neural algorithms by which neurons gain selectivity for interaural level difference in the brainstem of the barn owl (Tyto alba). Differences in the timing and in the level of sounds at the ears are used by this owl to encode, respectively, azimuthal and vertical position of sound sources in space. These two cues are processed in two parallel neural pathways. Below the level of the inferior colliculus, all neurons in the pathway that processes level differences show responses to this cue that are monotonic, and thus not selective for a particular level difference. Only in the inferior colliculus, which contains a map of auditory space, are neurons sharply tuned to specific interaural level differences. How are these response properties generated from those of the nuclei that provide input to the inferior colliculus? I show that the posterior subdivision of the nucleus ventralis lemnisci lateralis (VLVp) projects bilaterally to the lateral shell of the central nucleus of the inferior colliculus, the input stage to the map of auditory space. Both these nuclei are part of the pathway that processes interaural level differences. Manipulations of the responses in VLVp affected the responses to level differences in the inferior colliculus; responses to time differences were unaffected. By systematically increasing or decreasing neural activity in VLVp, I show that the VLVp on each side provides inhibition to the colliculus at large level differences. This results in a peaked response that is tuned to level differences in the inferior colliculus. Some cells in the lateral shell of the inferior colliculus appear to receive direct GABAergic inhibition from VLVp. I suggest that this circuitry and the algorithms it supports are the neural substrates that allow the barn owl to exploit level differences for computation of sound source elevation.

Acoustic Stimulation↗

PubMedDate not supplied

Functional neurotoxicity of drugs of abuse.

The epidemic growth of the use of controlled substances has brought their toxic effects to clinical attention. Several drugs of abuse are known to induce nerve cell toxicity after acute and chronic administration. In addition, it has been suggested that the three main classes of abused substances, namely psychostimulants, ethanol and opiates, also induce changes in the function of discrete neural pathways. These alterations may eventually be responsible for the loss of behavioral control often observed during the natural history of the addiction process. Therefore, biochemical and behavioral toxicity deserve equal attention. A complex neural network within the forebrain limbic system which has been characterized over the past few years seems to mediate drug-seeking behavior and maintain drug self-administration in rodents. A striking similarity has been observed between this circuit and the neural substrates of motivated behavior. This review focuses on the possibility that drugs of abuse may acquire significance as reinforcers by usurping the physiological role of this circuit which normally operates to ensure survival of the individual. This may represent a subtle mechanism through which drugs of abuse may induce behavioral toxicity even in the absence of nerve cell loss.

Animals↗

PubMed1993

Brain mechanisms and conscious experience.

The human brain enables a variety of unique mental capacities. Our special capacities for inference, personal insight into the reasons for our actions, deception, high level problem solving, for literally dozens of activities represent specialized systems that most likely reflect specialized neuronal circuits that have accumulated in our brain by selection processes over thousands of years of evolution. I believe many of these enriching capacities are not so much the advantageous computational products of a large neuropil as they are the product of a brain that has accumulated specific algorithms for adaptation. Our awareness, our consciousness of these capacities, is nothing more or less than a feeling about them. A correlate of this view is that there are many processes supporting human cognition of which we are neither aware nor conscious. When conscious appreciation or feeling is involved for a modality of sensation or action, neural pathways communicating this information must be intact, normally to the left hemisphere. This paper reviews evidence that supports this view of consciousness that distinguishes special human capacities and feelings about those capacities from the neural substrates that underlie these distinctions.

Animals↗

PubMed1990

Brain pathways of the chromatophore system in the squid Lolliguncula brevis.

Brain pathways controlling the chromatophores of the squid Lolliguncula brevis are described using cobalt iontophoresis. The results show several input and output pathways of the anterior and posterior chromatophore and lateral basal lobes. These connections allow coordination and modification of the chromatophore motor program throughout the motor pathway. Unlike other cephalopod species, there seems to be no direct input from the optic lobes to the lateral basal lobes in L. brevis. This species displays only a few simple patterns; therefore the underlying neural pathways for chromatophore control may be different from those of other cephalopods with more extensive patterning repertoires.

Animals↗

PubMed2004

Mate searching in Caenorhabditis elegans: a genetic model for sex drive in a simple invertebrate.

Much of animal behavior is regulated to accomplish goals necessary for survival and reproduction. Little is known about the underlying motivational or drive states that are postulated to mediate such goal-directed behaviors. Here, we describe a mate-searching behavior of the Caenorhabditis elegans male that resembles the motivated behaviors of vertebrates. Adult C. elegans males, if isolated from mating partners, will leave the area of a food source and wander about their environment in an apparent search for a mate. When mating partners are present on the food source, males do not wander but remain with them. This behavior is sexually dimorphic for C. elegans and two additional male/hermaphrodite species studied; for these species, hermaphrodites leave food significantly slower than males. In contrast, for three male-female species examined, both males and females left food, in two cases with similar frequency, suggesting coordinate evolution of behavioral dimorphism with hermaphroditism. We use a quantitative behavioral assay to show that C. elegans male mate searching is regulated by signals from hermaphrodites and by physiological signals indicating nutritional and reproductive status. We identify genes in the serotonin, insulin, and sex determination pathways that affect the rate of mate searching. These genes may contribute to physiological and reproductive regulatory mechanisms. Our results establish C. elegans as a model genetic animal with a simple nervous system in which neural pathways leading to a motivated behavior may be genetically dissected.

Animals↗

PubMed2003

[Relationships between the brain and the immune system].

The concept that the brain can modulate activity the immune system stems from the theory of stress. Recent advances in the study of the inter-relationships between the central nervous system and the immune system have demonstrated a vast network of communication pathways between the two systems. Lymphoid organs are innervated by branches of the autonomic nervous system. Accessory immune cells and lymphocytes have membrane receptors for most neurotransmitters and neuropeptides. These receptors are functional, and their activation leads to changes in immune functions, including cell proliferation, chimiotactism and specific immune responses. Brain lesions and stressors can induce a number of changes in the functioning of the immune system. All these changes are not necessarily mediated by the neuroendocrine system. They can also be dependent on autonomic nerve function. The communication pathways that link the brain to the immune system are normally activated by signals from the immune system, and they serve to regulate immune responses. These signals originate from accessory immune cells such as monocytes and macrophages and they are represented mainly by proinflammatory cytokines. Proinflammatory cytokines produced at the periphery act on the brain via two major pathways: (1) a humoral pathway allowing pathogen specific molecular patterns to act on Toll-like receptors in those brain areas that are devoid of a functional blood-brain barrier, the so-called circumventricular areas; (2) a neural pathway, represented by the afferent nerves that innervate the bodily site of infection and injury. In both cases, peripherally produced cytokines induce the expression of brain cytokines that are produced by resident macrophages and microglial cells. These locally produced cytokines diffuse throughout the brain parenchyma to act on target brain areas so as to organise the central components of the host response to infection (fever, neuroendocrine activation, and sickness behavior).

Animals↗

PubMed2000

Spinal cholinergic inhibition of the pressor response to muscle activation is mediated by muscarinic, but not nicotinic, receptors.

This study examined the influence of spinal muscarinic and nicotinic receptors on the cardiovascular adjustments to skeletal muscle activation in anesthetized cats. Microdialyzing into the L(7) dorsal horn increasing doses of the muscarinic receptor agonist bethanechol, but not the nicotinic receptor antagonist mecamylamine, reduced increases in mean arterial pressure (MAP) and heart rate (HR) during hindlimb contraction or passive stretch. Atropine administration accentuated the cardiovascular responses during contraction, but not during passive stretch. These data indicate that muscarinic, but not nicotinic, receptors at the dorsal horn level blunt the pressor response to muscle activity. Further, the data suggest that the two neural pathways involved in muscle contraction or stretch are anatomically distinct.

Acetylcholine↗

PubMed1990

The neural mechanism of declarative memory consolidation and retrieval: a hypothesis.

This paper proposes a new theory addressing the neural mechanism of declarative memory consolidation and retrieval. The premise of the theory is that the cortex is responsible for the storage of declarative memory while the medial temporal lobe is responsible for the consolidation and retrieval of declarative memory. The theory suggests that the medial temporal lobe can only accomplish its functions related to memory by hierarchically and cooperatively regulating the descending limbic system, including the hypothalamus, epithalamus, septum, mammillary bodies and the bed nucleus of the stria terminalis. These descending limbic structures, together with the amygdala, further send efferents to the four ascending NA, 5-HT, DA and ACh systems. It is these four ascending extrathalamic regulatory systems that provide the feedback neural pathways to the cortex and regulate the processes of memory consolidation and retrieval in the cortex. Therefore, the coupling of these descending limbic structures to the ascending NA, 5-HT, DA and ACh systems completes the neural circuits responsible for the consolidation and retrieval of new declarative memories. This neural mechanism of declarative memory consolidation and retrieval is universal to all species in higher mammals.

Animals↗

PubMed2006

Galanin: a novel therapeutic target for depression, anxiety disorders and drug addiction?

Galanin is a neuropeptide synthesized in many neuronal types including brainstem norepinephrine-producing cells of the locus coeruleus and the serotonin-producing neurons of the dorsal raphe nucleus. Galanin inhibits the firing of rodent norepinephrine, serotonin and dopamine neurons and reduces release of these neurotransmitters in forebrain target regions. The distribution of galanin and its receptors and its actions on monoamine signaling has fostered interest in this neuropeptide in the field of behavioral pharmacology and the potential role of galanin in the pathophysiology of neurological diseases such as Alzheimer's disease, epilepsy, stroke, and in psychiatric disorders such as anxiety, depression, and drug addiction, particularly withdrawal. In rodent models, expression of galanin in brain is altered by various stressors, while administration of galanin can modulate anxiety-like responses to stress. Emerging evidence further supports a role for galanin in the mediation of depression-related behaviors in rodents. Recently, galanin agonists have been shown to decrease behavioral signs of opiate withdrawal, which are thought to result from hyperactivation of brain stress pathways. Studies using genetically modified mice suggest that galanin normally plays a protective role against opiate reinforcement and withdrawal. The present article reviews current evidence on a potential role for galanin in modulating stress-related neural pathways and behaviors, and speculates on the therapeutic potential of targeting this galanin system for emotional disorders and opiate addiction.

Animals↗

PubMedDate not supplied

A cGMP-dependent protein kinase gene, foraging, modifies habituation-like response decrement of the giant fiber escape circuit in Drosophila.

The Drosophila giant fiber jump-and-flight escape response is a model for genetic analysis of both the physiology and the plasticity of a sensorimotor behavioral pathway. We previously established the electrically induced giant fiber response in intact tethered flies as a model for habituation, a form of nonassociative learning. Here, we show that the rate of stimulus-dependent response decrement of this neural pathway in a habituation protocol is correlated with PKG (cGMP-Dependent Protein Kinase) activity and foraging behavior. We assayed response decrement for natural and mutant rover and sitter alleles of the foraging (for) gene that encodes a Drosophila PKG. Rover larvae and adults, which have higher PKG activities, travel significantly farther while foraging than sitters with lower PKG activities. Response decrement was most rapid in genotypes previously shown to have low PKG activities and sitter-like foraging behavior. We also found differences in spontaneous recovery (the reversal of response decrement during a rest from stimulation) and a dishabituation-like phenomenon (the reversal of response decrement evoked by a novel stimulus). This electrophysiological study in an intact animal preparation provides one of the first direct demonstrations that PKG can affect plasticity in a simple learning paradigm. It increases our understanding of the complex interplay of factors that can modulate the sensitivity of the giant fiber escape response, and it defines a new adult-stage phenotype of the foraging locus. Finally, these results show that behaviorally relevant neural plasticity in an identified circuit can be influenced by a single-locus genetic polymorphism existing in a natural population of Drosophila.

Animals↗